Goi Sakamoto

Clinicopathologic Characteristics and Prognosis of Breast Cancer Patients Associated with Pregnancy and Lactation: Analysis of Case-Control Study in Japan

Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation were clarified by means of a case‐control study of matched non‐pregnant and non‐lactating patients with breast cancer. From 18 institutions in Japan, a total of 192 subjects with breast cancer diagnosed during pregnancy (72 cases) and lactation (120 cases) were collected between 1970 and 1988, accounting for 0.76% of all breast cancer patients. The duration of symptoms was longer and tumor size was larger in the study subjects. Although the disease‐free interval was longer than that in the control patients, the survival time was shorter. There was no characteristic difference in histologic type. Vascular invasion and lymph node metastasis were found more frequently in the subjects. The positive rates of estrogen receptor and progesterone receptor were lower in the subjects. The 5‐ and 10‐year survival rates of the study patients were 65% and 55%, respectively, and these survivals were significantly lower than those of the control (P < 0.001). The survival rates were poorer in the subjects, in accordance with stage and lymph node metastasis. The results suggest that most of the patients with breast cancer diagnosed during pregnancy and lactation are in a more advanced stage because of a delay in detection and diagnosis, and hence have unfavorable prognosis. Therefore, it is important to diagnose and treat early for improvement of prognosis in patients with breast cancer during pregnancy and lactation.

Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy

PURPOSE The clinicopathologic importance of a second estrogen receptor (ER), ER-beta, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-beta assay, probably because of the lack of standardized methodology, the presence of several ER-beta isotypes (ER-beta1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-beta status provides clinically useful information over what is already provided by the traditional ER-alpha/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues. PATIENTS AND METHODS Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti-ER-beta antibodies that detect ER-beta1-3 (ER-betaN), ER-beta1, and ER-betacx (ER-beta2). RESULTS Positive staining for ER-betaN or ER-beta1 was associated with significantly better survival. By contrast, ER-betacx status did not influence survival. In multivariate analysis, ER-beta1 status emerged as an independent predictor of recurrence and mortality. ER-beta1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-beta1 positivity was associated with significantly better survival in patients with ER-alpha-negative/PR-negative or ER-alpha-negative/PR-negative/human epidermal growth factor receptor 2-negative (triple-negative) tumors, which are widely believed to be hormone unresponsive, have poor prognosis, and require chemotherapy. CONCLUSION Immunohistochemical examination of ER-beta1 in addition to ER-alpha and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.

Mucinous carcinoma of the breast in Japan. A prognostic analysis based on morphologic features

In 175 women with mucinous carcinoma (MC) of the breast, the morphologic features, the clinicopathological features (age, tumor size, and nodal status) and prognoses were investigated. They were divided into two types, those with “unmixed type” (n = 140) showing no component of invasive ductal carcinoma (IDC) and “mixed type” (n = 35) including an IDC component. The unmixed type showed less frequent (P < 0.01) nodal involvement and a higher degree (P < 0.005) of extracellular mucus production than the mixed type. The presence of nodal metastases showed no correlation with the degree of mucus production. The 10‐year survival rate of the unmixed type (90.4%) was better (P < 0.001) than in the mixed type (66.0%). In the unmixed type, a higher level of mucus production showed trends toward a better prognosis, younger age and smaller tumor size (P < 0.01). In the mixed type, the degree of mucus production showed no significant correlation with either the age, tumor size, or prognosis. It is more important for the prognosis of patients with MC to have no IDC component than to show abundant mucus within the tumor.

In vitro and in vivo release of soluble erbB-2 protein from human carcinoma cells.

An enzyme‐linked immunosorbent assay (ELISA) was developed to measure soluble erbB‐2 protein in culture supernatants of various human cell lines and sera of patients suffering from recurrent breast carcinoma. Soluble erbB‐2 protein was demonstrated in culture supernatants of cell lines that expressed high levels of erbB‐2 protein as shown by western blot analysis of cell lysates. Increased levels of the protein, 40‐ to 190‐fold higher than in healthy controls, were demonstrated in sera of 3 out of 12 patients with breast carcinomas. On immunohistological study of tumor tissues from 9 patients, high immune reaction with the anti‐erbB‐2 protein antibody was observed in 2 cases. These were two of the three patients who had elevated levels of erbB‐2 protein in serum (a sample was not available from the third patient). These results raise the possibility that soluble erbB‐2 protein level in serum can be used as an indicator for spread of carcinomas that overexpress erbB‐2 protein.

Mapping of a new target region of allelic loss to a 2-cM interval at 22q13.1 in primary breast cancer.

Allelic losses on chromosome arm 22q are frequently observed in human meningiomas and in carcinomas of the colon, ovary, and breast. Among 140 primary breast cancers we examined for loss of heterozygosity (LOH) at 16 polymorphic loci on the long arm of chromosome 22, 56 (40%) showed LOH for at least one locus. Eleven of these tumors had retained heterozygosity for markers proximal to the NF2 locus but showed LOH for markers distal to NF2. Deletion mapping indicated a new common region of deletion, 2‐cM in extent, at q13.1 between Interleukin 2 receptor β (IL2RB) and D22S279. Our results raise the possibility that one or more tumor suppressor genes associated with breast cancer may exist at 22q13.1. Comparison of these results with clinicohistological data indicated that allelic losses on 22q tend to occur more frequently in tumors of malignant histological types. Genes Chromosomes Cancer 21:108–112, 1998.

Identification of Rad51 alteration in patients with bilateral breast cancer

AbstractThe human Rad51 gene, HsRAD51, is a homolog of RecA of Escherichia coli and functions in recombination and DNA repair. BRCA1 and BRCA2 proteins form a complex with Rad51, and these genes are thought to participate in a common DNA damage response path-way associated with the activation of homologous recombination and double-strand break repair. Additionally, we have shown that the pattern of northern blot analysis of the Rad51 gene is closely similar to those of the BRCA1 and BRCA2 genes. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancer. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer, one with synchronous bilateral breast cancer and the other with synchronous bilateral multiple breast cancer. In both patients, blood DNAs showed a G-to-A transition in the second nucleotide of codon 150, which results in the substitution of glutamine for arginine. As this alteration was not present in any patients with breast or colon cancer examined, we assume that this missense alteration is likely to be a disease-causing mutation.

Oral Uracil and Tegafur Compared With Classic Cyclophosphamide, Methotrexate, Fluorouracil As Postoperative Chemotherapy in Patients With Node-Negative, High-Risk Breast Cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial

PURPOSE The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer. PATIENTS AND METHODS Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS. RESULTS Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF. CONCLUSION RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Allelic Loss on Chromosome 1p Is Associated with Progression and Lymph Node Metastasis of Primary Breast Carcinoma

Frequent allelic losses on the short arm of chromosome 1 have been observed in a wide variety of human tumors. Cytogenetic and molecular genetic studies in breast carcinomas have shown frequent alterations on chromosome 1, involving loss of 1p or gain of 1q.

Duct endoscopy and endoscopic biopsy in the evaluation of nipple discharge

SummaryMicrodochectomy is usually performed on patients with nipple discharge caused by intraductal proliferative lesions, such as intraductal papilloma and carcinoma. But this operation often sacrifices large amounts of normal mammary gland even when the lesion is a benign intraductal papilloma a few millimeters in diameter. We have developed duct endoscopy for the mammary duct system, and have reliably performed biopsies for intraductal proliferative lesions intraductally. From June 1989 to April 1990, we examined 22 cases by duct endoscopy, and performed endoscopic biopsy in 16 cases. The method of endoscopic biopsy is as follows. First, a bougie is inserted, without anesthesia other than Xylocaine jelly, into the orifice of the duct to enlarge it. Second, the outer cylinder and the inner needle are inserted; then the inner needle is removed, and the endoscope is inserted. After examination, the outer cylinder is moved up to the lesion to be biopsied and the endoscope is taken out. Then a sample is taken into the outer cylinder by aspiration. We diagnosed 10 cases of benign lesion and 5 cases of malignant lesion by cytological and/or histological examination. In conclusion, endoscopic biopsy, aided by duct endoscopy, is a useful and harmless diagnostic procedure in the evaluation of nipple discharge.

Expression of GCDFP-15 and AR decreases in larger or node-positive apocrine carcinomas of the breast

Aims : Apocrine carcinoma of the breast is typically, though not always, positive for gross cystic disease fluid protein‐15 (GCDFP‐15). In order to clarify the clinical significance of GCDFP‐15 in apocrine carcinomas, GCDFP‐15 expression was examined in apocrine carcinomas of different stages and compared with clinicopathological factors. Apocrine lesions reportedly exhibit an unusual immunohistochemical status, expressing androgen receptors (AR) instead of oestrogen receptors (ER), progesterone receptors (PR), or bcl‐2. Their expression was also examined.